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Article: Network-based screening identifies sitagliptin as an antitumor drug targeting dendritic cells

TitleNetwork-based screening identifies sitagliptin as an antitumor drug targeting dendritic cells
Authors
Issue Date7-Mar-2024
PublisherBMJ Publishing Group
Citation
Journal for ImmunoTherapy of Cancer, 2024, v. 12, n. 3 How to Cite?
Abstract

Background Dendritic cell (DC)-mediated antigen presentation is essential for the priming and activation of tumor-specific T cells. However, few drugs that specifically manipulate DC functions are available. The identification of drugs targeting DC holds great promise for cancer immunotherapy.

Methods We observed that type 1 conventional DCs (cDC1s) initiated a distinct transcriptional program during antigen presentation. We used a network-based approach to screen for cDC1-targeting therapeutics. The antitumor potency and underlying mechanisms of the candidate drug were investigated in vitro and in vivo.

Results Sitagliptin, an oral gliptin widely used for type 2 diabetes, was identified as a drug that targets DCs. In mouse models, sitagliptin inhibited tumor growth by enhancing cDC1-mediated antigen presentation, leading to better T-cell activation. Mechanistically, inhibition of dipeptidyl peptidase 4 (DPP4) by sitagliptin prevented the truncation and degradation of chemokines/cytokines that are important for DC activation. Sitagliptin enhanced cancer immunotherapy by facilitating the priming of antigen-specific T cells by DCs. In humans, the use of sitagliptin correlated with a lower risk of tumor recurrence in patients with colorectal cancer undergoing curative surgery.

Conclusions Our findings indicate that sitagliptin-mediated DPP4 inhibition promotes antitumor immune response by augmenting cDC1 functions. These data suggest that sitagliptin can be repurposed as an antitumor drug targeting DC, which provides a potential strategy for cancer immunotherapy.


Persistent Identifierhttp://hdl.handle.net/10722/344229
ISSN
2023 Impact Factor: 10.3
2023 SCImago Journal Rankings: 3.728

 

DC FieldValueLanguage
dc.contributor.authorNg, Ian-Ian-
dc.contributor.authorZhang, Jiaqi-
dc.contributor.authorTian, Tingzhong-
dc.contributor.authorPeng, Qi-
dc.contributor.authorHuang, Zheng-
dc.contributor.authorXiao, Kaimin-
dc.contributor.authorYao, Xiyue-
dc.contributor.authorNg, Lui-
dc.contributor.authorZeng, Jianyang-
dc.contributor.authorTang, Haidong-
dc.date.accessioned2024-07-16T03:41:49Z-
dc.date.available2024-07-16T03:41:49Z-
dc.date.issued2024-03-07-
dc.identifier.citationJournal for ImmunoTherapy of Cancer, 2024, v. 12, n. 3-
dc.identifier.issn2051-1426-
dc.identifier.urihttp://hdl.handle.net/10722/344229-
dc.description.abstract<p><strong>Background</strong> Dendritic cell (DC)-mediated antigen presentation is essential for the priming and activation of tumor-specific T cells. However, few drugs that specifically manipulate DC functions are available. The identification of drugs targeting DC holds great promise for cancer immunotherapy.</p><p><strong>Methods</strong> We observed that type 1 conventional DCs (cDC1s) initiated a distinct transcriptional program during antigen presentation. We used a network-based approach to screen for cDC1-targeting therapeutics. The antitumor potency and underlying mechanisms of the candidate drug were investigated in vitro and in vivo.</p><p><strong>Results</strong> Sitagliptin, an oral gliptin widely used for type 2 diabetes, was identified as a drug that targets DCs. In mouse models, sitagliptin inhibited tumor growth by enhancing cDC1-mediated antigen presentation, leading to better T-cell activation. Mechanistically, inhibition of dipeptidyl peptidase 4 (DPP4) by sitagliptin prevented the truncation and degradation of chemokines/cytokines that are important for DC activation. Sitagliptin enhanced cancer immunotherapy by facilitating the priming of antigen-specific T cells by DCs. In humans, the use of sitagliptin correlated with a lower risk of tumor recurrence in patients with colorectal cancer undergoing curative surgery.</p><p><strong>Conclusions</strong> Our findings indicate that sitagliptin-mediated DPP4 inhibition promotes antitumor immune response by augmenting cDC1 functions. These data suggest that sitagliptin can be repurposed as an antitumor drug targeting DC, which provides a potential strategy for cancer immunotherapy.</p>-
dc.languageeng-
dc.publisherBMJ Publishing Group-
dc.relation.ispartofJournal for ImmunoTherapy of Cancer-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleNetwork-based screening identifies sitagliptin as an antitumor drug targeting dendritic cells-
dc.typeArticle-
dc.identifier.doi10.1136/jitc-2023-008254-
dc.identifier.scopuseid_2-s2.0-85187517693-
dc.identifier.volume12-
dc.identifier.issue3-
dc.identifier.eissn2051-1426-
dc.identifier.issnl2051-1426-

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